title: Lysosomal positioning coordinates cellular nutrient responses.
abstract: mTOR (mammalian target of rapamycin) signalling and macroautophagy (henceforth autophagy) regulate numerous pathological and physiological processes, including cellular responses to altered nutrient levels. However, the mechanisms regulating mTOR and autophagy remain incompletely understood. Lysosomes are dynamic intracellular organelles intimately involved both in the activation of mTOR complex 1 (mTORC1) signalling and in degrading autophagic substrates. Here we report that lysosomal positioning coordinates anabolic and catabolic responses with changes in nutrient availability by orchestrating early plasma-membrane signalling events, mTORC1 signalling and autophagy. Activation of mTORC1 by nutrients correlates with its presence on peripheral lysosomes that are physically close to the upstream signalling modules, whereas starvation causes perinuclear clustering of lysosomes, driven by changes in intracellular pH. Lysosomal positioning regulates mTORC1 signalling, which in turn influences autophagosome formation. Lysosome positioning also influences autophagosome-lysosome fusion rates, and thus controls autophagic flux by acting at both the initiation and termination stages of the process. Our findings provide a physiological role for the dynamic state of lysosomal positioning in cells as a coordinator of mTORC1 signalling with autophagic flux.
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Genetics, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY, UK.
authors.forename: Viktor I
authors.initials: VI
authors.lastname: Korolchuk
authors.forename: Shinji
authors.initials: S
authors.lastname: Saiki
authors.forename: Maike
authors.initials: M
authors.lastname: Lichtenberg
authors.forename: Farah H
authors.initials: FH
authors.lastname: Siddiqi
authors.forename: Esteban A
authors.initials: EA
authors.lastname: Roberts
authors.forename: Sara
authors.initials: S
authors.lastname: Imarisio
authors.forename: Luca
authors.initials: L
authors.lastname: Jahreiss
authors.forename: Sovan
authors.initials: S
authors.lastname: Sarkar
authors.forename: Marie
authors.initials: M
authors.lastname: Futter
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Menzies
authors.forename: Cahir J
authors.initials: CJ
authors.lastname: O'Kane
authors.forename: Vojo
authors.initials: V
authors.lastname: Deretic
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D001343:Autophagy / Q000502:physiology; D005502:Food; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D046912:Multiprotein Complexes; D011506:Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases